Abstract 5587: Ultra-deep targeted sequencing of cell-free DNA and patient-matched white blood cells for treatment response evaluation in patients with metastatic colorectal cancer
Authors: Iris van 't Erve, Jamie E. Medina, Alessandro Leal, Eniko Papp, Jillian Phallen, Vilmos Adleff, Elaine Jiayuee Chiao, Adith S. Arun, Karen Bolhuis, John K. Simmons, Aanavi Karandikar, Kenneth C. Valkenburg, Mark Sausen, Samuel V. Angiuoli, Robert B. Scharpf, Cornelis J. Punt, Gerrit J. Meijer, Victor E. Velculescu, Remond J. Fijneman
Journal: Cancer Research (2023)

Abstract Background: Treatment response monitoring of patients with metastatic colorectal cancer is currently performed by computed tomography (CT) imaging, which assesses tumor volume. Circulating tumor DNA (ctDNA) testing has the potential to replace or complement CT imaging by assessing the presence and abundance of tumor-specific mutations, allowing for personalized treatment and early adaptation of treatment regimens through risk stratification and the emergence of therapy resistance mutations. However, germline and clonal hematopoiesis-associated alterations can confound the identification of tumor-specific alterations in cell-free DNA (cfDNA), often requiring additional sequencing of tumor tissue. Aim: The present study assessed whether ctDNA-based treatment response monitoring could be performed in a tumor tissue-independent manner by combining ultra-deep targeted sequencing analyses of cfDNA with patient-matched white blood cell (WBC) derived DNA. Methods: In total, 183 cfDNA and 49 WBC samples, along with 28 tissue samples, from 52 metastatic colorectal cancer patients participating in the prospective phase III CAIRO5 clinical trial were analyzed using an ultra-deep targeted sequencing liquid biopsy assay. Results: The combined cfDNA and WBC analysis prevented the reporting of false positives due to germline or hematopoietic variants in 40% of patients. Patient-matched tumor tissue sequencing did not provide additional information. Longitudinal analyses of ctDNA were more predictive of overall survival than standard-of-care radiological response evaluation. ctDNA mutations related to primary or acquired resistance to the EGFR inhibitor panitumumab were identified in 42% of patients. Conclusions: Accurate ctDNA mutation detection by combined cfDNA and WBC genomic DNA analyses in a tumor tissue-independent manner mitigates sample logistics challenges in the clinical setting, and the application of this approach for evaluation of therapeutic response and resistance opens new avenues for early adaptation of treatment regimens. Citation Format: Iris van 't Erve, Jamie E. Medina, Alessandro Leal, Eniko Papp, Jillian Phallen, Vilmos Adleff, Elaine Jiayuee Chiao, Adith S. Arun, Karen Bolhuis, John K. Simmons, Aanavi Karandikar, Kenneth C. Valkenburg, Mark Sausen, Samuel V. Angiuoli, Robert B. Scharpf, Cornelis J. Punt, Gerrit J. Meijer, Victor E. Velculescu, Remond J. Fijneman. Ultra-deep targeted sequencing of cell-free DNA and patient-matched white blood cells for treatment response evaluation in patients with metastatic colorectal cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5587.